Moving beyond the T cell synapse for combination neoadjuvant immunotherapy in head and neck cancer

Locally advanced, HPV-unrelated HNSCC is associated with a high rate of therapeutic resistance following standard-of-care surgery and risk–adapted adjuvant radiation or chemoradiation. PD-1i and other ICIs are currently being tested in the definitive setting for the treatment of locally-advanced HNSCC. Unexpectedly, in JAVELIN, a large randomized phase 3 trial that compared adjuvant avelumab combined with standard chemoradiation to chemoradiation alone, avelumab failed to improve either disease-free survival (DFS) or overall survival in patients with locally-advanced HNSCC (17). However, this result may have been predicted by preclinical mouse studies, which demonstrated that neoadjuvant immunotherapy improves long-term survival and enhances antitumor immune responses compared with the same therapy administered in the adjuvant setting (18). Furthermore, Huang et al. (19), demonstrated that pCR or major pathologic response (MPR), less than 10% viable tumor cells, after a single dose of PD-1i was associated with improved DFS in patients with high-risk resectable stage III/IV melanoma. Pathologic responses were associated with accumulation of TILs, which, likewise, were associated with clinical benefits. The role of pathological response and its effect on clinical benefits was recently evaluated for 6 trials where neoadjuvant treatment was given to melanoma patients (n = 192) (20), in which the pCR rate translated to an overall survival benefit assessed at 2 years. In comparison to PD-1i alone, combination immunotherapy with neoadjuvant nivolumab and ipilimumab in patients with HNSCC appears to be more effective, resulting in 54% of treated patients being downstaged and an MPR rate of 14% (21). Although combination immunotherapy is a promising approach to enhance response rates, given the large number of biologic agents of various mechanisms, the number of combinations that can be tested far outstrips the resources available to test them.

To deepen pathologic responses and improve survival, future neoadjuvant combinations should test ICIs with other ICIs, costimulatory agonists, vaccines, chemotherapy, and/or radiation to increase the degree of tumor recognition by antigen-specific T cells and eliminate immunosuppressive mechanisms in the TME (Figure 1) (22). Cytokine secretion resulting from T cell recognition of their cognate antigen can result in differentiation of suppressive myeloid cells (i.e., M2 macrophages) into pro-inflammatory macrophages (M1) and dendritic cells, whereas chemokine secretion can promote recruitment of additional immune cells into the tumor. While T cell activation can generate immunosuppressive functions, such as upregulation of PD-L1 in nearby cells, PD-L1 in the TME is generally a good prognostic feature. Moreover, PD-L1 may make the tumor more responsive to checkpoint inhibition, possibly in combination with a myeloid-targeted therapy. In contrast, those tumors lacking preexisting T cell recognition also lack pro-inflammatory cytokines, therefore myeloid cells differentiate into T cell suppressive phenotypes (M2) with impaired tumor trafficking. In this case, ICIs are unlikely to benefit the patient without alternative interventions.

In contrast to the approach tested in JAVELIN, there has recently been a surge of interest in combining immunotherapy with hypofractionated stereotactic body radiation therapy (SBRT). In early stage lung cancer, neoadjuvant PD-1i combined with SBRT resulted in a 53% MPR, as compared with 6% for PD-1i alone (23). The proposed mechanisms of synergy observed with this approach include (a) the release of tumor antigens and damage-associated molecular patterns; (b) deletion of Tregs; (c) upregulation of antigen-processing machinery, MHC class I, and death receptors such as Fas and NKG2D; (d) cytokine and chemokine induction; and (e) enhanced immune cell trafficking (24). Relevant to the Redman et al. study, the addition of Galunisertib, a TGF-β type I receptor inhibitor, to diminish the immunosuppressive effects of TGF-β in the TME, improved pathologic response rates to chemoradiation in a neoadjuvant clinical trial in patients with locally advanced rectal cancer (25). Changes in CXCR3+ CD8+ T cell tumor trafficking and activation status that correlated with response were suggested as possible mechanisms for the observed increase in clinical activity (Figure 1). In another study of neoadjuvant immunoradiotherapy testing SBRT-plus-nivolumab in patients with locally advanced HNSCC, the combination resulted in a high rate of pCR and MPR (60% in HPV-unrelated patients), with clinical to pathologic downstaging in 90% of the patients enrolled (26).

Compared with adjuvant therapy, neoadjuvant, preoperative immunotherapy provides the opportunity to: (a) determine the on-treatment therapeutic response of an individual patient; (b) reduce the tumor burden prior to surgery and facilitate more limited surgery; (c) deintensify or eliminate the need for adjuvant therapy; and (d) study the effect of therapy on the TME and immune landscape. Time will tell whether pathologic response is an accurate surrogate for survival, but as demonstrated by Redman et al. (8), reversal of immunosuppression and determined pathologic responses to bintrafusp alfa were associated with neoepitope-specific tumor T cell responses, lower myeloid cell tumor infiltration in the pretreatment tumors, and better pathologic responses than observed with PD-1i alone. If validated in larger clinical data sets, the findings suggest that concurrent neoadjuvant inhibition of myeloid cell tumor trafficking or function may be a rational strategy to improve pathologic response and clinical outcome in patients with HPV-unrelated HNSCC.

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